Abstract：
Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. More than 40 genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. Mutations involving the same gene (e.g., FGFR1, PROK2/PROKR2, CHD7) were found to cause normosmic CHH and Kallmann syndrome (KS), with and without associated phenotypes, illustrating the coexistence of CHH with signs of other complex syndromes. The Witteveen-Kolk syndrome (WITKOS), caused by defects of the SIN3A gene, is a heterogeneous disorder characterized by distinctive facial features, microcephaly, short stature, delayed cognitive, and motor development. Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far.
A man with KS associated with mild syndromic features (S1) and a boy with global developmental delay, syndromic short stature, micropenis and cryptorchidism (S2), in whom common genetic defects associated with CHH and short stature had been previously excluded, were studied by either chromosomal microarray analysis or whole exome sequencing.
Rare SIN3A pathogenic variants were identified in these 2 unrelated patients with CHH phenotypic features. A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1, and a SIN3A nonsense rare variant (p.Arg471*) was detected in S2.
These findings lead us to propose a link between SIN3A defects and CHH, especially in syndromic cases, based on these 2 patients with overlapping phenotypes of WITKOS and CHH.
A man with KS associated with mild syndromic features (S1) and a boy with global developmental delay, syndromic short stature, micropenis and cryptorchidism (S2), in whom common genetic defects associated with CHH and short stature had been previously excluded, were studied by either chromosomal microarray analysis or whole exome sequencing.
Rare SIN3A pathogenic variants were identified in these 2 unrelated patients with CHH phenotypic features. A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1, and a SIN3A nonsense rare variant (p.Arg471*) was detected in S2.
These findings lead us to propose a link between SIN3A defects and CHH, especially in syndromic cases, based on these 2 patients with overlapping phenotypes of WITKOS and CHH.
摘要：
背景：先天性低促性腺激素性性腺功能减退症（CHH）是由GnRH缺乏引起的罕见疾病。已有40多个基因与CHH的发病机制有关,但是大多数病例仍然没有分子诊断。发现涉及相同基因（例如FGFR1，PROK2/PROKR2，CHD7）的突变会导致正常CHH和Kallmann综合征，有和没有相关的表型，说明CHH与其他复杂综合征的症状共存。Witteveen-Kolk综合征(WITKOS),由SIN3A基因的缺陷引起，是一种以独特的面部特征为特征的异质性疾病，小头畸形,身材矮小,认知和运动发育迟缓。尽管在这种综合征中已经报道了微阴茎和隐睾，到目前为止，WITKOS尚未与CHH正式联系。
方法：一名患有Kallmann综合征（KS）并伴有轻度综合征特征（S1）的男子和一名患有全球发育迟缓的男孩，综合征性身材矮小，小阴茎和隐睾（S2），以前排除了与CHH和身材矮小相关的常见遗传缺陷，通过染色体微阵列分析(CMA)或全外显子组测序(WES)进行研究。
结果：在这两个具有CHH表型特征的无关患者中发现了罕见的SIN3A致病变异。15q24.1处的550kb缺失，包括整个SIN3A基因，在S1中鉴定出，并且是SIN3A无义稀有变体（p。在S2中检测到Arg471*)。
结论：这些发现使我们提出了SIN3A缺陷与CHH之间的联系，尤其是在综合征病例中，基于这两个具有WITKOS和CHH重叠表型的患者。
方法：一名患有Kallmann综合征（KS）并伴有轻度综合征特征（S1）的男子和一名患有全球发育迟缓的男孩，综合征性身材矮小，小阴茎和隐睾（S2），以前排除了与CHH和身材矮小相关的常见遗传缺陷，通过染色体微阵列分析(CMA)或全外显子组测序(WES)进行研究。
结果：在这两个具有CHH表型特征的无关患者中发现了罕见的SIN3A致病变异。15q24.1处的550kb缺失，包括整个SIN3A基因，在S1中鉴定出，并且是SIN3A无义稀有变体（p。在S2中检测到Arg471*)。
结论：这些发现使我们提出了SIN3A缺陷与CHH之间的联系，尤其是在综合征病例中，基于这两个具有WITKOS和CHH重叠表型的患者。
